The long-term goal of Dr. Angela Ellison, the candidate for this Career Development Award, is to develop interventions that will improve the acute management of vaso-occlusive pain events (VOE) in sickle cell disease (SCD). As part of this award, Dr. Ellison will expand her research training to include skills in the area of pharmacogenomics through mentoring, a structured laboratory experience, completion of relevant coursework, participation in weekly seminars, attendance at national research conferences and completion of the proposed research project. The Children's Hospital of Philadelphia (CHOP) provides an outstanding environment for young-scientists to gain experience, formal instruction, and independence in designing and conducting patient oriented research. Dr. Ellison is receiving mentorship from outstanding clinical and basic scientists with expertise in applied genomics, clinical pharmacology, hematology and emergency medicine. The overall goal of her proposal is to determine the pharmacogenetic factors underlying the inter-individual variation in analgesic response to morphine among patients with SCD. The proposal has four specific aims. The first is to characterize the frequency and pattern of single nucleotide polymorphisms in key candidate genes (OPRM1, COMT, and UGT2B7) among African American subjects with SCD and determine if the identified polymorphisms are associated with ethnicity. The second aim is to develop a clear clinical phenotype of analgesic response in children with SCD. The third aim will determine if morphine administration and the resulting systemic exposure, determined for individual patients by pharmacokinetic measurements, is associated with altered analgesic response to morphine in children with SCD. The relationship between the identified polymorphisms and analgesic response will also be examined. The fourth aim is an exploratory aim to identify other genes which regulate or influence morphine response in children with SCD. We anticipate that these studies will uncover genetic variants that influence morphine sensitivity and that these variants, potentially through specific interactions with other genetic and/or environment factors, will have predictive power in guiding drug and dose selection for the management of VOE in sickle cell disease.